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J Neuroinflammation. 2013 Feb 26;10:30. doi: 10.1186/1742-2094-10-30.

Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain.

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1
Department of Pediatrics, Division of Neurology, David Geffen School of Medicine at UCLA, 22-474 MDCC in CHS, Los Angeles, CA 90095-1752, USA.

Abstract

BACKGROUND:

Inflammatory signaling elicited by prolonged seizures can be contributory to neuronal injury as well as adverse plasticity leading to the development of spontaneous recurrent seizures (epilepsy) and associated co-morbidities. In this study, developing rat pups were subjected to lithium-pilocarpine status epilepticus (SE) at 2 and 3 weeks of age to study the effect of anti-inflammatory drugs (AID) on SE-induced hippocampal injury and the development of spontaneous seizures.

FINDINGS:

We selected AIDs directed against interleukin-1 receptors (IL-1ra), a cyclooxygenase-2 (COX-2) inhibitor (CAY 10404), and an antagonist of microglia activation of caspase-1 (minocycline). Acute injury after SE was studied in the 2-week-old rats 24 h after SE. Development of recurrent spontaneous seizures was studied in 3-week-old rats subjected to SE 4 months after the initial insult.None of those AIDs were effective in attenuating CA1 injury in the 2-week-old pups or in limiting the development of spontaneous seizures in 3-week-old pups when administered individually. When empiric binary combinations of these drugs were tried, the combined targeting of IL-1r and COX-2 resulted in attenuation of acute CA1 injury, as determined 24 h after SE, in those animals. The same combination administered for 10 days following SE in 3-week-old rats, reduced the development of spontaneous recurrent seizures and limited the extent of mossy fiber sprouting.

CONCLUSIONS:

Deployment of an empirically designed 'drug cocktail' targeting multiple inflammatory signaling pathways for a limited duration after an initial insult like SE may provide a practical approach to neuroprotection and anti-epileptogenic therapy.

PMID:
23442201
PMCID:
PMC3599749
DOI:
10.1186/1742-2094-10-30
[Indexed for MEDLINE]
Free PMC Article
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